Historically, a number of substances have been proposed as the angiogenic factor. Some of the families of compounds having angiogenic activity include fibroblast growth factor, vascular endothelial growth factor (VEGF), angiogenin, platelet-derived endothelial cell growth factor, transforming growth factor- , transforming growth factor- , and tumor necrosis factor- . Vascular endothelial growth factor is thought to be a primary culprit. It is found in concentrations 40–100 times normal in the aqueous humor of patients with neovascular glaucoma.37 Tolentino and co-workers38 showed that intravitreal injection of VEGF can produce iris neovascularization and neovascular glaucoma in primates. Some consider that angiogenesis is most likely a process (not unlike the clotting or inflammatory cascades) involving several families of agents, including polypeptides, amines, lipids, and other low molecular weight compounds.

The above theory explains many observations about neovascular glaucoma. Diffusible molecules from the retina enter the anterior chamber through the pupil, with their highest concentration near this site. This may explain the initial appearance of rubeosis iridis at the pupillary margin.This mechanism also accounts for why rubeosis iridis and neovascular glaucoma are more common after cataract extraction with capsular disruption and after vitrectomy in eyes with vascular retinopathy. The lens and vitreous may serve as mechanical barriers to the diffusion of an angiogenic sub- stance.39–43 Furthermore, the vitreous humor apparently also contains an endogenous inhibitor of angiogenesis.44 Finally, vitrectomy and cataract surgery cause inflammation, which may further serve as a stimulus to neovascularization. Lastly, this theory explains the efficacy of panretinal photocoagulation or retinal cryoablation in neovascular glaucoma, treatments which destroy ischemic retina that had been synthesizing the angiogenic factor(s). Aiello and co-workers45 have found a marked decrease in VEGF in the vitreous of patients after panretinal photocoagulation.These treatments may also liberate inhibitory factors that counteract the vasoproliferative stimulus.46,47

Conditions and diseases commonly associated with neovascular glaucoma

Neovascular glaucoma is associated with a large number of diseases and conditions (Box 16–1). As noted above, most of these conditions have some relation to either retinal or ocular ischemia

Box 16–1  Diseases and conditions associated with neovascularization of the iris and neovascular glaucoma

Ocular vascular disease

Central retinal vein occlusion

Central retinal artery occlusion

Branch retinal vein occlusion

Branch retinal artery occlusion

Sturge-Weber syndrome with choroidal hemangioma

Leber’s miliary aneurysms

Sickle cell retinopathy

Diabetes mellitus

Extraocular disease

Carotid artery disease/ligation

Ocular ischemia

Aortic arch syndrome

Carotid-cavernous fistula

Giant cell arteritis

Pulseless disease

Assorted ocular diseases

Retinal detachment

Eales’ disease

Coats’ disease

Retinopathy of prematurity

Persistence and hyperplasia of the primary vitreous

Retinoschisis

Glaucoma

Open-angle

Angle-closure

Secondary

Norrie’s disease

Stickler’s syndrome

Trauma

Essential iris atrophy

Neurofibromatosis

Lupus erythematosus

Marfan’s syndrome

Recurrent hemorrhages

Vitreous wick syndrome

Ocular neoplasms

Malignant melanoma

Retinoblastoma

Optic nerve glioma associated with venous stasis

Metastatic carcinoma

Reticulum cell sarcoma

Medulloepithelioma

Squamous cell carcinoma conjunctiva

Angiomatosis retinae

Ocular inflammatory disease

Chronic uveitis

Endophthalmitis

Sympathetic ophthalmia

Syphilitic retinitis

Vogt-Koyanagi-Harada syndrome

Ocular therapy

Cataract excision (especially in diabetics)

Vitrectomy (especially in diabetics)

Retinal detachment surgery

Radiation

Laser coreoplasty

Modified from Gartner S, Henkind P: Neovascularization of the iris (rubeosis iridis), Surv Ophthalmol 22:291,48 1978 and Wand M: Neovascular glaucoma. In: Ritch R, Shields MB, Krupin T, editors: The glaucomas, 2nd edn., St Louis, Mosby, 1982.49

or to chronic inflammation. In a large comprehensive survey, diabetes mellitus was associated with about one-third of the cases of neovascular glaucoma; central retinal vein occlusion with another third; and a variety of conditions with the last third – with carotid occlusive disease being the most common in the last group.50 The discussion here is limited to a few of the more common entities,

such as central retinal vein occlusion and diabetes mellitus, from among a wide variety of predisposing conditions.48,49,51

Diabetes mellitus

Diabetes mellitus is one of the most common causes of neovascular glaucoma,52 accounting for approximately one-third of the cases. Neovascular glaucoma is usually seen in eyes with proliferative

diabetic retinopathy, but it can be seen in eyes with nonproliferative retinopathy if there are large areas of capillary nonperfusion.53 The prevalence of neovascular glaucoma is related to the duration of diabetes and may also be influenced by the presence of other vascular diseases such as hypertension. It is common for neovascular glaucoma to appear within 6 months of vitrectomy in diabetic patients,54–58 especially in aphakic eyes,59–61 in eyes with proliferative retinopathy, and in eyes with pre-existing rubeosis iridis. In similar fashion, diabetic neovascular glaucoma is a common occurrence after intracapsular cataract extraction, whether performed alone39,62 or in combination with vitrectomy. There is evidence that diabetic neovascular glaucoma is less common after extracapsular cataract extraction than after intracapsular cataract extraction,63 unless the capsule is ruptured, or zonular support is lost with exposure of vitreous (as seen with lax capsular support in pseudoexfoliation.) As noted previously, the lens and vitreous may act as mechanical barriers to the forward movement of angiogenic factors elaborated by the retina.The vitreous may also serve as an endogenous inhibitor of angiogenic stimuli.

It is especially important to emphasize the distinction between

rubeosis iridis and neovascular glaucoma in diabetic eyes. Rubeosis iridis is said to occur in 1–17% of diabetic eyes,64–66 and in 33–64%

of eyes with proliferative diabetic retinopathy.67,68 Clearly, the prevalence of rubeosis iridis is much higher than the prevalence of neovascular glaucoma. Rubeosis iridis may progress to neovascular glaucoma in some diabetic patients, but in others the condition remains stationary for long periods of time or even regresses.69 The rate of progression is much lower if the retina is treated with photocoagulation. If neovascular glaucoma develops in one eye of a diabetic patient, the fellow eye is at high risk if adequate retinal photocoagulation is not applied.

Central retinal vein occlusion

Central retinal vein occlusion is among the commonest cause of neovascular glaucoma. It is estimated that about 30% of patients who suffer a central retinal vein occlusion develop neovascular glaucoma. More comprehensive investigations have done much to clarify this association. Hayreh70,71 has carefully discriminated central retinal vein occlusion into two types – ischemic and nonischemic (venous stasis retinopathy). Approximately three-quarters of central retinal vein occlusions are non-ischemic, and one-quar- ter are ischemic.72 Yet neovascular glaucoma occurs in 18–86% of

eyes with ischemic vein occlusions, as opposed to 0–4% of eyes with non-ischemic occlusions.73–77 According to a large study, about 40%

of patients with ischemic central retinal vein occlusion will develop neovascular glaucoma.78 The distinction between ischemic and nonischemic vein occlusions is usually made by judging the degree of retinal capillary non-perfusion (capillary dropout) on fluorescein angiography.79,80 Other signs of ischemia include 10 or more cotton wool spots in the retina, an absent perifoveal capillary network on fluorescein angiography, arteriovenous transit time greater than 20 seconds, leaky iris vessels on angiography, and a reduced B:A wave ratio on electroretinography. Eyes with ischemic central retinal vein occlusions should receive panretinal photocoagulation (or cryoablation if no laser is available) to reduce the incidence of neovascular glaucoma. Careful follow-up is mandated even in those with the non-ischemic type because of the observation that one-third of eyes with central retinal vein occlusion and good perfusion at the onset show signs of ischemia by 3 years.81

Neovascular glaucoma may present anywhere from 2 weeks to 2 years following a central retinal vein occlusion.82 However, the condition often presents about 3 months after central retinal vein

occlusion: hence its reputation as the ‘100-day glaucoma’.Younger patients with central retinal vein occlusions often have associated vascular diseases, such as hypertension or one of the collagen vascular disorders.

Older patients with central retinal vein occlusions often have associated glaucoma or elevated IOP. Elevated IOP or glaucoma has

been reported in 10–23% of eyes that developed a central retinal vein occlusion.83,84 In most cases the underlying glaucoma is open

angle or exfoliative in type, but there have been a few reports of central retinal vein occlusion following angle-closure glaucoma.85 The underlying glaucoma is often masked because these eyes may have a low IOP for weeks to months following vein occlusion.86 In addition, the low IOP may reflect transient poor perfusion of the ciliary body. The presence of pre-existing POAG increases the risk of neovascular glaucoma after central retinal vein occlusion despite adequate prophylactic laser treatment: adequate treatment of the pre-existing glaucoma does not prevent the onset of neovascularization. Furthermore, pre-existing open-angle glaucoma may make any subsequent neovascular glaucoma more refractory to treatment.87 It is also common for fellow eyes to have elevated IOP or to develop it at a later time. Although a true causative role for elevated IOP in central retinal vein occlusion has not been established, it is probably wise to treat fellow eyes with elevated IOP with ocular hypotensive agents. One case-control study does support elevated IOP as a risk factor in central retinal vein occlusion along with systemic hypertension and male gender.88 Green and co-workers89 proposed that posterior bowing of the lamina cribrosa in glaucoma creates a mechanical obstruction that impedes the venous outflow and contributes to venous stasis and/or occlusion.

Carotid occlusive disease

Carotid artery disease is considered the third most common cause of neovascular glaucoma. Neovascular glaucoma has been reported after carotid artery ligation90,91 and idiopathic carotid artery obstruction.The obstruction can be unilateral or bilateral and can involve the common carotid artery or the internal carotid artery.92–95 Carotid artery obstruction does not cause neovascular glaucoma in all cases because there is usually sufficient collateral flow to prevent widespread retinal ischemia. Carotid artery palpation and auscultation should be performed in all cases of central retinal vein occlusion. Neovascular glaucoma associated with carotid artery disease often has a confusing presentation and a variable course. If anterior segment ischemia is severe, the vessels on the iris may be less visible, and the IOP may be normal or even low despite extensive neovascular closure of the angle. These eyes often suffer wide swings in IOP, depending on the perfusion to the ciliary body.96 Patients who undergo surgery to relieve or bypass carotid artery obstruction may experience a dramatic rise in IOP when the ciliary body blood supply improves and aqueous humor formation increases. Panretinal photocoagulation may be less successful in eliminating iris neovascularization in patients with carotid artery obstruction because the anterior segment of these eyes is also ischemic and is not affected by retinal ablation techniques.

Ocular ischemic syndrome

Several authors have described a condition called chronic ocular ischemic syndrome that includes signs of transient ischemic attacks; ocular motor disturbances; midperipheral retinal hemorrhages; neo-

vascularization of the iris; and, late in its course, corneal striae and hypotony.97,98 Although the term was initially used to describe

obstruction of the carotid artery, extracarotid causes have also been identified, including abnormalities of carotid flow without